Mechanical Heart Valves: Contraindication for Dabigatran Therapy

Mary Ann E. Zagaria, PharmD, MS, CGPIndependent Senior Care Consultant Pharmacist and President of MZ Associates, Inc.,Norwich, New Yorkwww.mzassociatesinc.comRecipient of the Excellence in Geriatric Pharmacy Practice Award from the Commission for Certification in Geriatric Pharmacy.

2/19/2014

US Pharm. 2014;39(2)32-34.

In the United States, it is estimated that more than 95,000 patients undergo heart valve replacement each year.1
It has become increasingly common to treat hemodynamically significant
aortic or mitral valve disease with the implantation of prosthetic
cardiac valves, made either from synthetic material, referred to as a mechanical prosthesis, or from biologic tissue, referred to as a bioprosthesis.1
Treatment for valvular disease includes a plan to 1) decrease the risk
of further heart damage; 2) manage symptoms with medication, if
necessary (TABLE 1); 3) repair or replace
the valve, if necessary; and 4) communicate to both patient and
caregivers the steps for management and self-care, as well as and the
importance of follow-up care.

Valve repair and valve replacement are
the available choices once the determination has been made that a
diseased heart valve needs treatment.2 Valve repair
aims to preserve the valve and leaflets and can involve minimal to more
extensive surgery. Most often, repair is possible for mitral valve
regurgitation and tricuspid valve regurgitation. Valve replacement
can involve a less invasive procedure such as transcatheter aortic
valve implantation (TAVI) or may require a more involved surgery such as
the Ross procedure, where the diseased aortic valve is replaced by the
patient’s own pulmonary valve, or the insertion of a new tissue valve or
manufactured valve.2 Most valve replacements involve the aortic and mitral valves.2

Indications for Mechanical Heart Valves

General indications for mechanical heart valves are outlined in TABLE 2.
Of note, valvular aortic stenosis (AS) in older adults is usually
caused by stiffening, scarring, and calcification of the aortic valve
leaflets; aortic valve replacement (AVR) is the procedure of choice for
symptomatic elderly patients with severe AS, including octogenarians.1,3
Causes of acute aortic regurgitation (AR) in older adults may include
infective endocarditis, rheumatic fever, aortic dissection, and trauma
secondary to prosthetic valve surgery, among others.3 Chronic
AR in older adults may be due to valve leaflet disease (secondary to
AS, rheumatoid arthritis, ankylosing spondylitis, other conditions) or
aortic root disease (associated with systemic hypertension, rheumatoid
arthritis, systemic lupus erythematosus).3 Age-associated increased prevalence of AR has been linked to aortic valve thickening.4-6

Complications of Valve Replacement

Complications of mechanical valves are outlined in TABLE 2.
Acute failure of a prosthetic aortic valve causes a rapidly progressive
left ventricular volume overload; myocardial ischemia may follow acute
AR, even in the absence of coronary artery disease.1 In
general, bioprosthetic valves have functional properties (e.g.,
resistance to thrombosis) more similar to native valves; mechanical
valves tend to be thrombogenic and require lifelong anticoagulation.1
Prosthetic valve thrombosis (PVT) and arterial thromboembolism are more
common in mechanical valves than in bioprosthetic valves; PVT is
increased with valves in the mitral position and in patients on
subtherapeutic anticoagulation.1

The type of prosthesis chosen is therefore determined by the patient’s likely longevity and ability to tolerate anticoagulation.7 Proper anticoagulation usually results in a thrombosis rate in all valves within 0.1%-5.7% per patient-year.1
To minimize this risk, oral anticoagulation alone or with the addition
of antiplatelet drugs has been used; the effectiveness and safety of the
latter strategy is considered an important issue.8
Mechanical valves are not prone to structural valve deterioration, so
most remain functional for 20-30 years, compared to 30%-35% of
bioprostheses, which fail within 10-15 years.1

Dabigatran

Dabigatran etexilate, the prodrug for the
active moiety dabigatran, is a direct thrombin inhibitor currently
indicated to reduce the risk of stroke and systemic embolism in patients
with nonvalvular atrial fibrillation.9-12 Since thrombin
enables the conversion of fibrinogen into fibrin during the coagulation
cascade, its inhibition prevents the development of a thrombus; both
free and clot-bound thrombin and thrombin-induced platelet aggregation
are inhibited by the active moiety.11 After the discovery of warfarin, dabigatran was the first oral anticoagulant to be approved in 50 years.9Clinicians
had hoped that a novel oral direct clotting inhibitor would provide
either similar or advanced protection for patients with mechanical heart
valves without the warfarin-associated need for strict and frequent
monitoring, dietary restrictions, or multiple medication interactions.13

Postmarketing Experience:A
randomized clinical trial (RE-ALIGN), however, showed that dabigatran’s
side effects were even more problematic than those of warfarin in
patients with mechanical heart valves. In this trial, 252 patients who
had an aortic or mitral valve replacement were randomly assigned to
either dose-adjusted warfarin or dabigatran 150, 220, or 300 mg twice
daily.14 The study was terminated early secondary to the
occurrence of significantly more thromboembolic events (valve
thrombosis, stroke, transient ischemic attack, and myocardial
infarction) and excessive major bleeding (predominantly postoperative
pericardial effusions requiring intervention for hemodynamic compromise)
with dabigatran compared with warfarin. Changes to dabigatran’s
prescribing information ensued.14

Black Box Warning:
An FDA black box warning was added to the medication label warning
against using dabigatran and similar medications in patients with
mechanical heart valves as a result of this clinical trial, which was
funded by Boehringer Ingelheim, the maker of dabigatran (Pradaxa).10,11,13
Additionally, the following adverse reactions have been identified
during postapproval use of dabigatran: angioedema, thrombocytopenia, and
esophageal ulcer.11 It is not always possible to reliably
estimate the frequency of these reactions or establish a causal
relationship to drug exposure since they have been reported voluntarily
from a population of uncertain size.11 Pharmacists are
encouraged to familiarize themselves with MedWatch: The FDA Safety
Information and Adverse Event Reporting Program for clinically important
safety information and reporting of serious problems with human medical
products.

Risk of Bleeding:Dabigatran
increases the risk of bleeding and can cause significant and possibly
fatal bleeding. Signs or symptoms of blood loss (e.g., a drop in
hemoglobin and/or hematocrit or hypotension) should be promptly
evaluated.10,11 This agent should be discontinued in patients
with active pathologic bleeding; risk factors for bleeding include
concomitant use of medications that increase the risk of bleeding (e.g.,
antiplatelet agents, heparin, fibrinolytic therapy, chronic use of
nonsteroidal anti-inflammatory drugs [NSAIDs]).10,11 Seniors
may be at greater risk owing to comorbidities requiring expansive and
complex medication regimens that include many of the offending
concomitant medications noted above. The elderly are a high-risk
population for adverse effects from NSAIDs; up to 60% of elderly people
can develop peptic ulceration and/or hemorrhage asymptomatically.15 Renal impairment increases anticoagulant activity and half-life.

There is no reversal agent available for
dabigatran. While hemodialysis can remove dabigatran, clinical
experience is limited with regard to hemodialysis as a treatment for
bleeding.10,11 While their use has not been evaluated,
activated prothrombin complex concentrates, recombinant factor VIIa, or
concentrates of factors II, IX, or X may be considered; protamine
sulfate and vitamin K are not expected to affect dabigatran
anticoagulant activity.10,11 The administration of platelet
concentrates should be considered where thrombocytopenia is present or
long-acting antiplatelet drugs have been used.10,11

Conclusion

Pharmacists are encouraged to keep
abreast of postmarketing randomized clinical trials for information to
support or challenge premarketing safety and efficacy data for the
direct thrombin inhibitor dabigatran, including updated dosing
guidelines, drug interactions, and specific monitoring recommendations.

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